Study of transcription factors that regulate the development, maintenance and aging of conventional and innate T cells. Transcription factors T Cell Factor TCF-1 and beta-catenin regulate the development of NKT cells and differentiation into NKT1, NKT2 and NKT17 subsets. TCF1 is required for the generation of all NKT cells, as deletion of TCF1 reduces the number to NKT cells. Reduction in the development of NKT cells results from reduced lifetime of precursor thymocytes and reduced rearrangement and expression of T cell receptor TCR Valpha14-Jalpha18 distal genes that are required for NKT cell generation and selection. Beta-catenin in conjunction with TCF1 is required for differentiation of NKT2 cells that preferentially produce IL-4 and IL-13. NKT2 cells are implicated in causing asthma, and accordingly, mice with enhanced expression of beta-catenin in T cells promote IL-25-dependent asthma in transgenic mice. Ongoing work focuses on molecular mechanisms involved in these events. Expression of TCF1 declines as TCR gamma-delta T cells mature in the thymus. However, as induction of TCF1 in thymocytes was shown to be down-stream of Notch1 signals and, since Notch1 is not essential for gamma-delta T cell development, this raised the question of TCF1 regulation in these cells. Ongoing work indicates that TCF1 expression maybe regulated by E-proteins in gamma-delta T cells. Ongoing work will focus on understanding E-protein dependent regulation of TCF1 in gamma-delta T cells. Study of innate and adaptive immune cells in chronic neurological diseases, including EAE, Parkinsons and Alzheimers disease is also ongoing. TCF1-deficient mice show augmented response to MOG-peptide induced EAE, the mouse model for human Multiple Sclerosis. Beta-catenin expression is also functionally relevant in initiation and propagation of disease. Ongoing work will determine the identity and nature of T cell response to these diseases.